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Transition-state docking of flunitrazepam and progesterone in cytochrome P450

Rydberg, Patrik LU ; Hansen, Sine Myrup; Kongsted, Jacob LU ; Norrby, Per-Ola; Olsen, Lars and Ryde, Ulf LU (2008) In Journal of Chemical Theory and Computation 4(4). p.673-681
Abstract
We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly... (More)
We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs. better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
4
issue
4
pages
673 - 681
publisher
The American Chemical Society
external identifiers
  • wos:000254710700014
  • scopus:58149107172
ISSN
1549-9618
DOI
10.1021/ct700313j
language
English
LU publication?
yes
id
ad74f420-622b-4f87-8e9b-f0f351561fd0 (old id 1207454)
date added to LUP
2008-08-27 13:47:47
date last changed
2017-06-11 03:34:38
@article{ad74f420-622b-4f87-8e9b-f0f351561fd0,
  abstract     = {We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs. better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software.},
  author       = {Rydberg, Patrik and Hansen, Sine Myrup and Kongsted, Jacob and Norrby, Per-Ola and Olsen, Lars and Ryde, Ulf},
  issn         = {1549-9618},
  language     = {eng},
  number       = {4},
  pages        = {673--681},
  publisher    = {The American Chemical Society},
  series       = {Journal of Chemical Theory and Computation},
  title        = {Transition-state docking of flunitrazepam and progesterone in cytochrome P450},
  url          = {http://dx.doi.org/10.1021/ct700313j},
  volume       = {4},
  year         = {2008},
}